Several family planning strategies are currently widespread in the United States including sterilization, abstinence, abortion and contraception. Of these four birth control methods, contraception is the most widely utilized. Oral contraceptives and barrier methods are popular and efficacious but have significant shortcomings. Currently available oral contraceptives modulate hormone levels and are documented to be associated with nausea, headaches, breast tenderness, weight gain, irregular bleeding, mood changes, and more significant side effects including increased risks of cardiovascular disease and breast cancer, especially in women over 35. Currently available oral contraceptives may also lead to adverse cross reactions with other drugs, including cyclosporine, dantrolene and warfarin. Furthermore, currently available oral contraceptives lose efficacy when combined with antibiotics. Barrier methods, while safe, have failure rates approaching 20%. Other less common contraceptive methods, such as immunization of women against sperm polypeptides (see U.S. Pat. No. 5,935,578), may result in irreversible immunity to sperm and permanent reduction in fertility. There is a clear need for increased availability of and improvements in contraceptives that offer superior safety, efficacy, convenience, acceptability, affordability and reversibility.
A Ca+2 channel, CatSper1, has recently been cloned (see U.S. Patent Pub No. 2004/0157292). CatSper1 is naturally expressed exclusively in the testis and not in other tissues such as the brain, heart, kidney or the immune system. Targeted disruption of the gene results in male sterility in otherwise normal mice. Sperm hyperactivity in CatSper1 −/− (knockout) mice is dramatically decreased, and cyclic AMP induced Ca+2 influx is abolished in the sperm of mutant mice.
The invention provides novel agents that inhibit sperm hyperactivity. In one embodiment, the novel agents are antagonists of the CatSper1 channel which specifically inhibit sperm hyperactivity. The restricted expression of CatSper1 and its essential role in fertility make the CatSper1 channel antagonists promising contraceptive agents with high potency and decreased side effects.